Patent GB-933168-A (GB)
Title: Improvements in or relating to n-(2-phenyl-cyclopropyl)-carbamates and -formamide derivatives
IPC: A61K31/27
Filed: 1961-09-08
Abstract: The invention comprises compounds having the formula <FORM:0933168/IV(a)/1> in which R1 is phenyl, chlorophenyl, fluorophenyl, trifluoromethylphenyl, lower alkylphenyl, dichlorophenyl or di-loweralkylphenyl; R2 is hydrogen, lower alkoxy, benzyloxy or phenethoxy; and R3 is hydrogen or lower alkyl (lower alkyl and lower alkoxy are defined as having 1-4 carbon atoms).  The formamides are prepared by reacting the appropriate 2-phenylcyclopropylamine with ethyl formate.  The carbamates are prepared (1) by reacting the appropriate 2-phenylcyclopropylamine with the appropriate ester of chloroformic acid or (2) by reacting the appropriate styrene with ethyl diazoacetate, saponifying the resultant ethyl 2-phenylcyclopropanecarboxylate and reacting the carboxylic acid obtained with (a) a lower alkyl haloformate to give the cyclopropyl mixed anhydride which is treated with sodium azide to give the cyclopropyl acid azide (b) a chlorinating agent such as thionyl chloride or phosphorus pentachloride to give the acid chloride which is treated with sodium azide to give the cyclopropyl acid azide or (c) diazomethane and refluxing the resultant methyl ester with hydrazine hydrate in ethanol to give the hydrazide which is diazotised with hydrochloric acid and sodium nitrite to give the azide, and the azide heated to give the isocyanate which is then heated with the appropriate alcohol to give the carbamate; the isocyanates referred to under (2) may also be used to prepare the 2-phenylcyclopropylamines referred to under (1).  The carboxylates or carboxylic acids referred to under (2) above may be separated into the cis and trans isomers.  In the examples, (1) trans-N-(2-phenylcyclopropyl) formamide is prepared from trans-2-phenylcyclopropylamine and ethyl formate, (2) trans-ethyl N-(2-phenylcyclopropyl) carbamate is prepared from trans-2-phenylcyclopropylamine and ethyl chloroformate, (3) trans-benzyl N-(2-phenylcyclopropyl) carbamate is prepared from trans-2-phenylcyclopropylamine and benzyl chloroformate (4) t-butyl N-(2-phenylcyclopropyl) carbamate is prepared from 2-phenylcyclopropylamine and t-butyl chloroformate (5) benzyl N-methyl-N-(2-phenylcyclopropyl) carbamate is prepared from N-methyl-2-phenylcyclopropylamine and benzyl chloroformate (6) transbenzyl N-[2-(4-trifluoromethylphenyl) cyclopropyl] carbamate is prepared by reacting 4-trifluoromethylstyrene and ethyl diazoacetate to give ethyl 2-(4-trifluoromethylphenyl) cyclopropane carboxylate, hydrolysing this ester to give a mixture of the cis and trans isomeric acids which are separated by fractional crystallisation, reacting the trans isomer with diazomethane and converting the methyl ester thus produced to the acid hydrazide followed by diazotization and decomposition to give methyl N-[2-(4-trifluoromethyphenyl) cyclopropyl] carbamate, hydrolysing the carbamate to yield trans-2-(4-trifluoromethylphenyl)- cyclopropylamine which is then reacted with benzyl chloroformate (7) trans-benzyl N-[2-(4-chlorophenyl) cyclopropyl] carbamate is prepared by reacting 4-chlorostyrene and ethyl diazoacetate and separating by distillation the trans-ethyl 2-(4-chlorophenyl) cyclopropanecarboxylate which is then hydrolysed to give the acid, reacting the acid with thionyl chloride to yield the acid chloride which is heated with sodium azide and the resulting isocyanate reacted with benzyl alcohol (8) benzyl N-[2-(2,5-dichlorophenyl)-cyclopropyl] carbamate is prepared from 2-(2,5-dichlorophenyl)-cyclopropylisocyanate (9) phenethyl N-[2-(4-fluorophenyl)-cyclopropyl] carbamate is prepared from 4-fluorostyrene and phenethyl alcohol (10) benzyl N-[2-(3-tolyl) cyclopropyl] carbamate is prepared from 2-(3-tolyl)cyclopropylamine and benzyl chloroformate (11) benzyl N-butyl-N-[2-(2,4-xylyl) cyclopropyl] carbamate is prepared by reacting 2-(2,4-xylyl) cyclopropylamine, N-butyl bromide and sodium amide to give N-butyl-2-(2,4-xylyl) cycloproplyamide which is then reacted with benzyl chloroformate (12) n-propyl N-ethyl-N-[2-(4-butylphenyl) cyclopropyl] carbamate is prepared by reacting 2-(4-butylphenyl) cyclopropylamine, ethyl bromide and sodium amide to give N-ethyl-2-(4-butylphenyl) cyclopropylamine which is then reacted with n-propyl chloroformate (13) N-[2-(3,4-dichlorophenyl) cyclopropyl] carbamate is prepared from 2-(3,4-dichlorophenyl) cyclopropyl isocyanate and benzyl alcohol (14) cisphenethyl N-(2-phenylcyclopropyl carbamate is prepared from phenethyl chloroformate and cis-2-phenylcyclopropylamine and (15) trans-benzyl N-(2-phenylcyclopropyl) carbamate is prepared by reacting trans-2-phenylcyclopropane carboxylic acid with ethyl chloroformate followed by sodium azide, and the azide thus formed decomposed to the isocyanate which is then reacted with benzyl alcohol.  The compounds of the invention are useful as anti-depressant agents having potent monoamine oxidase inhibiting activity together with a low order of toxicity.  Reference has been directed by the Comptroller to Specification 873,018.